David W Hein1, Mark A Doll1. 1. Department of Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
Abstract
AIM: Solithromycin is a new macrolide antibiotic for the potential treatment of bacterial pneumonia. MATERIALS & METHODS: Solithromycin N-acetylation by human NAT1 and NAT2 was investigated following recombinant expression in yeast and in cryopreserved human hepatocytes from rapid, intermediate and slow acetylators. RESULTS: Solithromycin exhibited over twofold higher affinity for recombinant human NAT2 than NAT1. Apparent maximum velocities for the N-acetylation of solithromycin catalyzed by the NAT2 allozyme associated with rapid acetylators were significantly (p < 0.01) higher than by the NAT2 allozymes associated with slow acetylators. Robust gene dose responses (rapid>intermediate>slow acetylators) were exhibited in cryopreserved human hepatocytes in situ following incubation with 100 μM solithromycin. CONCLUSION: Solithromycin is N-acetylated by human NAT1 and NAT2 and the role of the NAT2 acetylation polymorphism on solithromycin metabolism may be concentration dependent.
AIM: Solithromycin is a new macrolide antibiotic for the potential treatment of bacterial pneumonia. MATERIALS & METHODS:Solithromycin N-acetylation by humanNAT1 and NAT2 was investigated following recombinant expression in yeast and in cryopreserved human hepatocytes from rapid, intermediate and slow acetylators. RESULTS:Solithromycin exhibited over twofold higher affinity for recombinant humanNAT2 than NAT1. Apparent maximum velocities for the N-acetylation of solithromycin catalyzed by the NAT2 allozyme associated with rapid acetylators were significantly (p < 0.01) higher than by the NAT2 allozymes associated with slow acetylators. Robust gene dose responses (rapid>intermediate>slow acetylators) were exhibited in cryopreserved human hepatocytes in situ following incubation with 100 μM solithromycin. CONCLUSION:Solithromycin is N-acetylated by humanNAT1 and NAT2 and the role of the NAT2 acetylation polymorphism on solithromycin metabolism may be concentration dependent.
Entities:
Keywords:
N-acetyltransferase 2; acetylation polymorphism; cryopreserved human hepatocytes; solithromycin
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